Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology

Roberts, V.G.; Morgan, T. O.; Bednarek, Paula H.; Morita, Mayu; Burton, Graham J.; Lo, Jamie O.; Frias, A.I

doi:10.1093/humrep/dex301

Cited by 132 publications

(114 citation statements)

References 35 publications

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“…Here, we provide evidence that platelet-derived factors impair placental βhCG synthesis. Although trophoblast plugs in uterine arteries obstruct maternal arterial blood flow to the developing placental chorionic tissue during the first trimester of human pregnancy, maternal platelets may pass through narrow intertrophoblastic gaps that have been suggested to enable initial microvascular flux by 7 weeks of gestation [1]. We show platelets on the surface of placental villi from 5 weeks gestation onwards, where they either adhered directly on the apical surface of the syncytiotrophoblast or on initial perivillous fibrinoid.…”

Section: Discussionmentioning

confidence: 71%

“…Placental extravillous trophoblasts invade the maternal decidua, where they accumulate and form cellular plugs that obstruct maternal arterial blood flow to the developing placental villous tissue until the end of the first trimester of pregnancy. However, presence of loosely cohesive trophoblast plugs with clear capillary-sized channels with flow toward the intervillous space has been suggested to enable initial microvascular flux by 7 weeks of gestation [1]. These channels seem to be the first signs of subsequent plug disintegration and complete remodeling of maternal spiral arteries into wide-bore, lowresistance conduits.…”

Section: Introductionmentioning

confidence: 99%

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Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

et al. 2019

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During histiotrophic nutrition of the embryo, maternal platelets may be the first circulating maternal cells that find their way into the placental intervillous space through narrow intertrophoblastic gaps within the plugs of spiral arteries. Activation of platelets at the maternal-fetal interface can influence trophoblast behavior and has been implicated in serious pregnancy pathologies. Here, we show that platelet-derived factors impaired expression and secretion of the human chorionic gonadotropin beta-subunit (βhCG) in human first trimester placental explants and the trophoblast cell line BeWo. Impaired βhCG synthesis was not the consequence of hampered morphological differentiation, as assessed by analysis of differentiation-associated genes and electron microscopy. Platelet-derived factors did not affect intracellular cAMP levels and phosphorylation of CREB, but activated Smad3 and its downstream-target plasminogen activator inhibitor (PAI)-1 in forskolin-induced BeWo cell differentiation. While TGF-β type I receptor inhibitor SB431542 did not restore impaired βhCG production in response to platelet-derived factors, Smad3 inhibitor SIS3 interfered with CREB activation, suggesting an interaction of cAMP/CREB and Smad3 signaling. Sequestration of transcription co-activators CBP/p300, known to bind both CREB and Smad3, may limit βhCG production, since CBP/p300 inhibitor C646 significantly restricted its forskolin-induced upregulation. In conclusion, our study suggests that degranulation of maternal platelets at the early maternal-fetal interface can impair placental βhCG production, without substantially affecting morphological and biochemical differentiation of villous trophoblasts. Key messages & Maternal platelets can be detected on the surface of the placental villi and in intercellular gaps of trophoblast cell columns from gestational week 5 onwards. & Platelet-derived factors impair hCG synthesis in human first trimester placenta. & Platelet-derived factors activate Smad3 in trophoblasts. & Smad3 inhibitor SIS3 interferes with forskolin-induced CREB signaling. & Sequestration of CBP/p300 by activated Smad3 may limit placental hCG production.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

et al. 2019

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“…It is known that the placenta can become infected by 9-12 weeks gestation and perhaps even earlier, when maternal blood first enters the intervillous space and begins to perfuse the placenta at 8-9 weeks gestation. [28][29][30] A recent modeling study used placental histopathology results, parity, and transmission intensity data to estimate that 63% of infections become established by the end of the first trimester, with the highest risk occurring at the end of the third month. 31 The risk of PM correlates with the frequency and parasite density of maternal P. falciparum infections during pregnancy, but even low-density infections (ie those that are detectable by sensitive PCR or LAMP tests but not blood smear) can result in placental infection.…”

Section: Risk Factors and Timing Of Placental Infectionmentioning

confidence: 99%

The immune response to malaria in utero

Feeney

2019

Immunological Reviews

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Malaria caused by Plasmodium falciparum is a leading killer of infants and children. Efforts to develop a protective vaccine have been hindered by the parasite's numerous evasion strategies, which include the induction of immunoregulatory mechanisms in the human host.Indeed, several promising vaccine candidates that induce robust protection in malaria-naive populations have been shown to have much lower efficacy when administered to individuals residing in endemic settings, 1,2 suggesting that immunomodulatory mechanisms induced by prior malaria exposure may pose a critical barrier to vaccine-mediated protection. In endemic regions, many individuals are first exposed to malaria in utero, when P. falciparum-infected red blood cells sequester in the placenta and parasite antigens cross the syncytiotrophoblast barrier, gaining entry into the fetal circulation.Therefore, even during the neonatal period, vaccination may be influenced by prior malaria exposure. Here, we examine the consequences of in utero antigen exposure for fetal immune development and postnatal immunity. The worldwide burden posed by malaria-related complications of pregnancy is profound. More than 125 million pregnancies occur annually in regions at risk for malaria transmission, 3 and one in four pregnant women in sub-Saharan Africa have evidence of infection with malaria at parturition. 4 Although most placental malaria (PM) infections are attributable to P. falciparum, recent evidence indicates that P.vivax is also associated with poor pregnancy outcomes, and some data suggest that it too may sequester in the placenta. 5,6 Pregnancy-associated malaria results in tremendous obstetrical and pediatric morbidity, AbstractMalaria causes tremendous early childhood morbidity and mortality, providing an urgent impetus for the development of a vaccine that is effective in neonates. However, the infant immune response to malaria may be influenced by events that occur well before birth. Placental malaria infection complicates one quarter of all pregnancies in Africa and frequently results in exposure of the fetus to malaria antigens in utero, while the immune system is still developing. Some data suggest that in utero exposure to malaria may induce immunologic tolerance that interferes with the development of protective immunity during childhood. More recently, however, a growing body of evidence suggests that fetal malaria exposure can prime highly functional malariaspecific T-and B-cells, which may contribute to postnatal protection from malaria. In utero exposure to malaria also impacts the activation and maturation of fetal antigen presenting cells and innate lymphocytes, which could have implications for global immunity in the infant. Here, we review recent advances in our understanding of how various components of the fetal immune system are altered by in utero exposure to malaria, discuss factors that may tilt the critical balance between tolerance and adaptive immunity, and consider the implications of these findings for malaria prevention strateg...

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“…Furthermore, in experimental rat studies it appears SonoVue™ does not affect the permeability of the placental barrier, with no leakage of molecules observed [17]. The plugging of spiral arteries in the placenta has been previously investigated using another agent, Definity™ (Lantheus Medical Imaging, Billerica, MA) [18] with no reported deleterious effects. Another agent Levovist™ (Schering, Berlin) was also used successfully to observe twin-twin transfusion [13].…”

mentioning

confidence: 99%

“…Darüber hinaus zeigt sich in experimentellen Studien mit Ratten, dass SonoVue keinen Einfluss auf die Permeabilität der Plazentaschranke hat und dass keine austretenden Moleküle beobachtet wurden [17]. Das Plugging der Spiralarterien der Plazenta wurde zuvor mit einem anderen Agens, Definity™ (Lantheus Medical Imaging, Billerica, MA), untersucht [18], ohne dass schädliche Wirkungen berichtet wurden. Ein weiteres Mittel, Levovist™ (Schering, Berlin), wurde ebenfalls erfolgreich zur Beobachtung des fetofetalen Transfusionssyndroms eingesetzt [13].…”

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Contrast enhanced ultrasound (CEUS) in Pregnancy: Is this the last frontier for microbubbles?

Sidhu¹,

Huang²,

Fang³

2020

Ultraschall in Med

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Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology

Abstract: This project was supported by the Oregon Health and Science University Knight Cardiovascular Institute, Center for Developmental Health and the Struble Foundation. There are no competing interests.

Cited by 132 publications

References 35 publications

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

The immune response to malaria in utero

Contrast enhanced ultrasound (CEUS) in Pregnancy: Is this the last frontier for microbubbles?

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